ICAM-4 (LW blood group glycoprotein) is an erythroid-specific membrane component that belongs to the family of intercellular adhesion molecules and interactsThe main physiological function of red blood cells (RBCs), 1 which encapsulate hemoglobin, is to ensure the respiratory gases transport throughout the human body. However, the recent demonstration that mature RBCs express a growing number of adhesion molecules, many of which exhibit blood group specificities (1-3), reinforces the necessity to revisit the functional interaction of RBCs with leukocytes, platelets, and vascular endothelium under normal and pathological conditions.It is interesting that many RBC adhesion molecules contain protein domains characteristic of the immunoglobulin superfamily, suggesting some recognition function. These molecules might participate in the normal RBC physiology by playing a role during erythropoiesis (differentiation, maturation, enucleation, release), self-recognition mechanisms, red cell turnover, and cell aging through cellular interactions with counter

Protein structures are valuable tools to understand protein function. Nonetheless, proteins are often considered as rigid macromolecules while their structures exhibit specific flexibility, which is essential to complete their functions. Analyses of protein structures and dynamics are often performed with a simplified three-state description, i.e., the classical secondary structures. More precise and complete description of protein backbone conformation can be obtained using libraries of small protein fragments that are able to approximate every part of protein structures. These libraries, called structural alphabets (SAs), have been widely used in structure analysis field, from definition of ligand binding sites to superimposition of protein structures. SAs are also well suited to analyze the dynamics of protein structures. Here, we review innovative approaches that investigate protein flexibility based on SAs description. Coupled to various sources of experimental data (e.g., B-factor) and computational methodology (e.g., Molecular Dynamic simulation), SAs turn out to be powerful tools to analyze protein dynamics, e.g., to examine allosteric mechanisms in large set of structures in complexes, to identify order/disorder transition. SAs were also shown to be quite efficient to predict protein flexibility from amino-acid sequence. Finally, in this review, we exemplify the interest of SAs for studying flexibility with different cases of proteins implicated in pathologies and diseases.

To cite this article: Bertrand G, Martageix C, Jallu V, Vitry F, Kaplan C. Predictive value of sequential maternal anti-HPA-1a antibody concentrations for the severity of fetal alloimmune thrombocytopenia. J Thromb Haemost 2006; 4: 628-37.Summary. Background: Fetal/neonatal alloimmune thrombocytopenia results from maternal immunization against fetal platelet alloantigens (HPAs), and the major risk is intracranial hemorrhage. The severity of thrombocytopenia increases in subsequent pregnancies, and antenatal therapy has been developed. Until now, the fetal status can only be assessed by fetal blood sampling, which carries a risk of fetal loss or premature delivery. Objectives: To develop non-invasive methods to gain information on the fetal condition. Patients/ methods: Quantification of the maternal anti-HPA-1a alloantibody concentration was performed with a standardized monoclonal antibody-specific immobilization of platelet antigens (MAIPA) procedure for 43 mothers. A correlation between this concentration and the fetal/neonatal platelet counts was studied. Results: (i) Before antenatal therapy, there was a significant correlation between maternal anti-HPA-1a concentrations ‡250 AU mL )1 and fetal thrombocytopenia (2-66 · 10 9 L )1) whatever the gestational age (Fisher's exact test P ¼ 0.0021). (ii) During subsequent pregnancies, we observed a decrease of the maternal anti-HPA-1a concentration for 14/19 women. Just before delivery, all women had anti-HPA-1a concentrations <250 AU mL )1. In four cases, there was a therapy failure and the severely thrombocytopenic babies required postnatal therapy. Conclusion: The maternal anti-HPA-1a concentration could provide obstetricians with clinically useful information concerning the appropriateness and the timing of invasive monitoring procedures. However, though we observed a tendency toward a decrease in maternal antibody concentration after treatment, this finding does not allow us to draw any conclusions on the effectiveness of therapy.

Integrin αIIbβ3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), αIIbβ3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of αIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures. The most flexible region of Calf-1 (with highest B-factor) is rather a rigid region encompassed into two deformable zones. Each mutated structure barely showed any modifications at the mutation sites while distant conformational changes were observed. These unexpected results question the relationship between molecular dynamics and allostery; and the role of these long-range effects in the impaired αIIbβ3 expression. This method is aimed at studying all αIIbβ3 sub-domains and impact of missense mutations at local and global structural level.

This analysis confirms that anti-HPA-9bw (Max(a)) FMAIT is not uncommon and was found to be approximately 2 percent of our confirmed FMAIT cases. It is a clinically severe syndrome that requires prompt diagnosis, albeit difficult, and maternal PLT transfusion therapy. Laboratory investigation of a suspected FMAIT case should be carried out in a specialist laboratory well-experienced in optimal testing. Appropriate management and antenatal therapy should be considered for successive pregnancies to prevent fetal bleeding.